The present invention relates generally to the treatment of disease states involving immunological factors and more particularly to methods and materials for alleviation of symptoms of nonanaphylactic disorders wherein disease pathology results in whole or part from the victim's own humoral and/or cell-mediated immune response to one or more immunogenic substances.
Disease states involving immunological factors may be seen to broadly comprise (1) immunodeficiency diseases, and (2) disorders wherein tissue injury occurs as a result of a humoral or cell-mediated response to immunogens (e.g., antigens) of endogenous or exogenous origin. This latter group of immunological disorders is frequently referred to as involving immune "hypersensitivity", with the numerous disease states comprehended by the term classified according to four hypersensitivity "reaction" types.
Type I reactions (frequently referred to as anaphylactic, immediate-type, atopic, reagenic, or IgE-mediated hypersensitivity reactions) generally result from the release of pharmacologically active substances such as histamine, slow-reacting substance of anaphylaxis (SRS-A), and eosinophilic chemotactic factor (ECF) from IgE-sensitized basophils and mast cells after contact with a specific exogenous antigen. Disease states in which Type I reactions play a role include allergic extrinsic asthma, seasonal allergic rhinitis, systemic anaphylaxis, and the like.
Type II reactions (also referred to as cytotoxic, cytolytic complement-dependent or cell-stimulating hypersensitivity reactions) result when antibody reacts with antigenic components of cells or tissue elements or with an antigen or hapten which has become intimately coupled to cells or tissue. Disease states with which Type II reactions are associated include autoimmune hemolytic anemia, erythroblastosis fetalis and Goodpasture's disease.
Type III reactions (also referred to as toxic complex, soluble complex, or immune complex hypersensitivity reactions) result from the deposition of soluble circulating antigen-antibody complexes in vessels or in tissues, with accompanying acute inflammatory reactions at the site of immune complex deposition. Prototypical Type III reaction disorders include Arthus reaction, serum sickness, systemic lupus erythematosis, and certain types of glomerulonephritis.
Type IV reactions (frequently called cellular, cell-mediated, delayed, or tuberculin-type hypersensitivity reactions) are caused by sensitized T-lymphocytes which result from contact with a specific antigen. Examples of diseases cited as involving Type IV reactions are contact dermatitis and allograft rejection.
Of particular interest in consideration of the present invention are those immunological disorders, especially prominent in humans, which are commonly referred to as "autoimmune" diseases. While the classification originated to distinguish immune disorders involving reaction against "self" or endogenous antigens from those involving reaction against exogenous antigens, significant controversy exists over the criteria for establishing a particular disease as autoimmune in origin. Autoantibodies can frequently be demonstrated in a large number of individuals who are free of autoimmune disease and autoimmune diseases such as rheumatic heart disease appear to involve, inter alia, cross-reactive immune responses to antigens of clearly exogenous origins (Streptococcus sp.). The designation of a particular disease as an autoimmune disorder is often subjectively based on (1) presence of some evidence of an antigen-antibody reaction including an endogenous antigenic substance, (2) judgement that the immunologic findings are not merely secondary to some other disease state, and (3) the lack of other identifiable causes for the disorder.
While autoimmune disorders are frequently associated with Type II hypersensitivity reactions, there exists evidence of involvement of Type III and Type IV reactions in some autoimmune diseases. Essentially as a matter of definition, immunological disorders of the "anaphylactic" or IgE-mediated type (i.e., Type I hypersensitivity reactions) are not classified as autoimmune due to the clear involvement of clearly exogenous antigenic substances.
Autoimmune diseases are frequently characterized by means of their involvement of single organ or single cell-types or involvement of multiple organs or tissue systems. (Due to the frequent involvement of either connective tissue and blood vessels in the diseases of the latter, systemic, type, these have frequently been referred to as "collagen," or "collagen-vascular" or "connective tissue" diseases.)
Diseases frequently designated as single organ or single cell-type autoimmune disorders include: Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy. Diseases often designated as involving systemic autoimmune disorder include: systemic lupus erythematosis, rheumatoid arthritis, Sjoren's syndrome, Reiter's syndrome, polymyositisdermatomyositis, systemic sclerosis, polyarteritis nodosa and multiple sclerosis.
It is unfortunately the case that the treatment of many of the above-noted autoimmune disorders is, at best, primitive and seldom effective in alleviating disease symptoms for significant periods of time. Progressive degenerative autoimmune diseases such as systemic lupus erythematosis, systemic sclerosis, polyarteritis, polymyositis and multiple sclerosis are usually treated by administration of high doses of corticosteroids to alleviate discomfort due to inflammation of tissues. Immunosuppressant therapy has proven to be of little value. Drug therapy (see, e.g., U.S. Pat. Nos. 3,864,481 and 4,113,858) has provided no consistent alleviation of the frequently painful symptoms nor altered substantially the general prognosis of progressive debilitation and death.
The following somewhat disparate items of information concerning the state of the art in immunology are of considerable interest to the background of the invention.
Histamine [4-(2-aminoethyl)-imidazole or .beta.-imidazolylethylamine] is a chemical substance possessing pronounced biological activities. It is a powerful stimulant of gastric secretion and constrictor of smooth muscle. It is a vasodilator and large doses cause a relatively rapid fall in blood pressure. It is frequently noted to be liberated by epithelial cells upon traumatic injury or stimulation by antigenic substances. Its storage in and release from mast cells and basophil granules and its role in Type I hypersensitivity reactions have been the subject of extensive study. At present, its clinical use is principally as a stimulant in diagnosis of impairment of gastric secretion. From time to time, therapeutic uses have been proposed including administration for alleviation of certain kinds of headache symptoms. With the single exception of an experimental study into use of homeopathic doses in treatment of multiple sclerosis [Jonez, "My Fight to Conquer Multiple Sclerosis," Messner (1952)] it has not been employed in the treatment of any autoimmune disorders.
To the extent that autoimmune diseases have been the subject of etiological investigation, it has frequently been the case that, with varying degrees of precision, one or more endogenous or exogenous immunogens has been associated with participation in formation of circulating antibodies. See, e.g., Holborow, et al., "Immunoassays in Autoimmune Disease" appearing at pp. 277-288 in "Immunoassays for the 80's," Voller, et al., eds., University Park Press, Baltimore (1981). Results of such studies have been principally of diagnostic significance and have been of little use in formulating therapeutic regimens for the diseased patients. As one example, there have been numerous reports of isolation of circulating (humoral) antiviral antibodies from multiple sclerosis patients, including antibodies against vaccinia, rubella, herpes simplex, varicella-zoster, mumps, Epstein-Barr virus, adenovirus and even canine distemper virus. Despite the lack of any evidence of viral particle involvement in lesions or cerebrospinal fluids of multiple sclerosis patients, one of the most consistently reported antiviral antibodies found in such patients has been antimeasles virus antibody. Further, the applicant and his co-workers were able to employ homogenized lymphocytes of multiple sclerosis patients to provoke formation of heterologous species antibodies which, in turn, have been found to be exceptionally useful in the development of diagnostic procedures. See, e.g., U.S. Pat. No. 4,294,818. This lymphocyte-associated immunogen, (i.e., the antigen responsible for formation of the highly specific antibodies reactive with sera of all multiple sclerosis patients) has not yet been purified to homogeneity and characterized, nor has it been employed in any form in any known therapeutic regimen for alleviation of multiple sclerosis symptoms. As another example, the rheumatoid arthritis disease state is frequently proposed as having an autoimmune basis on the ground of a characteristic presence of circulating "RF" (rheumatoid factor), an anti-immunoglobulin antibody directed at IgG. In seropositive patients, it is proposed that RF, which can undergo a complement fixing interaction with IgG, is involved in inducing and maintaining chronic synovitis.
Finally, over the last twenty or so years, a small body of information has developed concerning a therapeutic regimen known as "provocative neutralization" therapy. See, e.g., Miller, "Food Allergy, Provocative Testing and Injection Therapy," Charles C. Thomas, Springfield, Ill. (1972); Miller, Annals of Allergy, 38, pp. 185-191 (1977); Miller, Trans. Am. Soc. Opth. & Otolar. Allergy, 14, pp. 159-168 (1974); and Miller, Clinical Med., 81, pp. 16-19 (1974). Briefly put, the therapeutic scheme involves subcutaneous administration of a known "causative" agent of a particular disease state in amounts comprising the patient's maximum tolerated intradermal dose. This dose is defined as the smallest dilution (i.e., highest concentration) of the substance which will produce a negative wheal when employed in a standard skin test injection procedure. The proposed mode of operation of this regimen is through modulation of sub-populations of T-lymphocytes. Initial successes for this treatment procedure were reported in the context of relief of headache symptoms correlated with food allergies. Subsequently, relief of symptoms of acute influenza infection has been reported to attend provocative neutralization treatments with live attenuated influenza virus. Further, relief from herpes simplex Type I infection has been reported for patients treated with influenza virus.